Heart Failure Prevalence Rates and Its Association with Other Cardiovascular Diseases and Chronic Kidney Disease: SIMETAP-HF Study

Introduction and objectives: Heart failure (HF) is a major health problem that causes high mortality and hospitalization rates. This study aims to determine the HF prevalence rates in populations aged both ≥18 years and ≥50 years and to assess its association with cardiovascular diseases and chronic kidney disease. Methods: A cross-sectional observational study was conducted in a primary care setting, with a population-based random sample of 6588 people aged 18.0–102.8 years. Crude and adjusted prevalence rates of HF were calculated. The associations of renal and cardiometabolic factors with HF were assessed in both populations using univariate, bivariate and multivariate analysis. Results: The HF crude prevalence rates were 2.8% (95%CI: 2.4–3.2) in adults (≥18 years), and 4.6% (95%CI: 4.0–5.3) in the population aged ≥ 50 years, without significant differences between males and females in both populations. The age- and sex-adjusted prevalence rates were 2.1% (male: 1.9%; female: 2.3%) in the overall adult population, and 4.5% (male: 4.2%; female: 4.8%) in the population aged ≥ 50 years, reaching 10.0% in the population aged ≥ 70 years. Atrial fibrillation, hypertension, low estimated glomerular filtration rate (eGFR), coronary heart disease (CHD), stroke, sedentary lifestyle, and diabetes were independently associated with HF in both populations. A total of 95.7% (95%CI: 92.7–98.6) of the population with HF had an elevated cardiovascular risk. Conclusions: This study reports that HF prevalence increases from 4.5% in the population over 50 years to 10% in the population over 70 years. The main clinical conditions that are HF-related are sedentary lifestyle, atrial fibrillation, hypertension, diabetes, low eGFR, stroke, and CHD.


Introduction
Heart failure (HF) is a complex clinical syndrome that results from any structural and/or functional cardiac disturbances. Any cardiac pathology such as myocardial dysfunction (systolic and/or diastolic), heart valve disease, pericarditis, endocarditis, cardiac rhythm and conduction disturbances can cause or contribute to HF [1][2][3].
HF is usually preceded by diseases or conditions which, in turn, may be the cause of other alterations [1][2][3][4] (Figure S1 Supplementary Materials). The most prevalent causes of HF have changed over time [4,5] and are probably different depending on the economic level of different countries [6]. In developed countries, the main causes associated with HF are coronary heart disease (CHD) and arterial hypertension (HTN) [1][2][3][4][5][6].
On the other hand, patients with HF tend to accumulate other comorbidities (CHD, atrial fibrillation [AF], atrial flutter, peripheral arterial disease, stroke, HTN, anemia, obesity, hypercholesterolemia, diabetes mellitus [DM], rheumatoid arthritis, chronic obstructive pulmonary disease and chronic kidney disease [CKD]), either individually or grouped (mean 3.9 comorbidities per patient, with a range of 0 to 9), and this is more frequent in patients with HF with preserved ejection fraction compared to those with reduced ejection fraction [6]. The presence and control of these comorbidities influence the results and quality of life of patients with HF.
HF diagnosis carries an increased risk of morbidity and mortality. HF is a wellrecognized public health problem worldwide that causes an increasing health and economic burden due to numerous hospital admissions and high mortality [7,8]. The age-adjusted incidence of HF is decreasing in developed countries, possibly due to better therapeutic management of the disease, although its overall incidence is increasing due to population ageing [7][8][9][10][11][12].
HF prevalence rates range from 1% to 2% of the adult population. Prevalence increases with age, from less than 1% for those younger than 55 years to >10% in those older than 70 years [8][9][10][11][12][13][14][15][16]. It is likely that the true prevalence of HF is higher because patients with HF are not recognized or diagnosed in a primary care setting, especially those with preserved ejection fraction [17].
A SIMETAP-HF study was designed to determine the crude and adjusted prevalence rates of HF both in the adult population (≥18 years) and in the population older than 50 years and to assess its association with other cardiovascular diseases and CKD.

Methods
SIIMETAP-HF is a sub-study of the SIMETAP study [18], a multicenter cross-sectional observational study, authorized by the Health Service of the Community of Madrid (SER-MAS according to its initials in Spanish), which 121 physicians participated in. The physicians were selected competitively to reach the necessary sample size and belonged to 64 primary care centers (25.6% from de SERMAS healthcare centers). Simple random sampling of 5.45% of the target population aged 18 years and over (194,073 adults) assigned to GPs was performed using random numbers drawn from the Excel function RAND.BETWEEN (bottom, top). Terminally ill patients or those with cognitive impairments, institutionalized persons, and pregnant women were excluded as per protocol. After a response rate of 62.9%, 6588 study subjects were selected with informed consent and with the necessary clinical and laboratory data to be evaluated. The researchers entered study data from January to December 2015, and collected data based on the most recent biochemical parameters determined from blood and urine tests taken during the previous year. For the purposes of this study, registry of HF diagnosis ( Qualitative variables were analyzed using percentages, a chi-square test, and odds ratios, with a 95% confidence interval (CI). The Shapiro-Wilk test was used to check the data fitting to normal distribution for quantitative variables. If the variables showed normal distribution, they were analyzed using the arithmetic mean, standard deviation (SD) and Student's t-test or analysis of variance. The median and interquartile range (IQR) of age were determined. Prevalence rates were determined in populations aged ≥18, ≥50, ≥60, and ≥70 years of age. The age-and sex-adjusted prevalence rates were calculated by the direct method, using standardized ten-year age groups of the Spanish population as of January 2015 according to the National Institute of Statistics [19].
Bivariate and multivariate analyses were performed in populations aged ≥18 years and ≥50 years. To assess the individual effect of comorbidities and cardiovascular risk factors (CVRFs) on the dependent variable HF, multivariate logistic regression analysis was performed using the backward stepwise method. Initially, all the variables that showed association in the univariate analysis up to a p-value of <0.10 were introduced into the model, except for erectile dysfunction because it affects only men and CUN-BAE-obesity [20] and metabolic syndrome (MetS) [21] because both variables integrate some factors or criteria assessed independently in the analysis (Table S1, Supplementary Materials). Subsequently, the variable that contributed least to the fit of the analysis was eliminated at each step. All tests were considered statistically significant if the two-tailed p-value was <0.05. The Statistical Package for the Social Sciences was used for the statistical analysis.

HF Prevalence Rates
The crude and adjusted prevalence rates of HF in populations aged ≥18, ≥50, ≥60, and ≥70 years are shown in Table 1. The differences in prevalence rates between males and females were non-significant both globally (≥18 years) and by age group (Figure 1). The distribution of HF prevalence rates by ten-year age group increased according to the polynomial function y = 0.0085x 2 − 0.046x + 0.0497 (R 2 = 0.911). The prevalence rates were anecdotal in the population aged <50 years ( Figure 1).

Analysis of Populations ≥18 Years with and without HF
The median (IQR) ages of the populations with and without HF were 80.9 (72.0-88.7) years and 54.3 (41.4-67.2) years, respectively, with the difference in mean (SD) ages ] years) between both populations being significant (p < 0.001) ( Table 2). The difference in the female percentage (0.6% [95%CI: −6.7-7.9]) between the populations with and without HF was non-significant (p = 0.868) ( Table 3). In the population with HF, the difference in mean (SD) age between males (78.8 [10.2] years) and females (76.4 [12.2] years) was significant (p = 0.040).    All quantitative clinical variables were significantly higher in the population with HF than in the population without HF, except for diastolic blood pressure, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, low-density lipoprotein cholesterol (LDL-C), non-HDL-C/HDL-C, ALT, and estimated glomerular filtration rate (eGFR), which were significantly higher in the population without HF. The differences in triglycerides (TG), very-low-density lipoprotein cholesterol (VLDL-C), TG/HDL-C, and AST were non-significant ( Table 2).
All the ORs of the CVRFs and comorbidities showed a significant association with HF, except for overweight and prediabetes, whose differences were non-significant. The ORs for smoking, alcoholism, and low, moderate, and high cardiovascular risk (CVR) showed a significant association with the population without HF. A total of 95.7% [95%CI: 92.7-98.6]) of the population with HF had a high or very high CVR according to SCORE [22] and SCORE-OP [23] (Table 3). The multivariate analysis showed that AF, HTN, low eGFR, CHD, stroke, low HDL-C, sedentary lifestyle, and DM were independently associated with HF (Table 4).

Analysis of Populations ≥50 Years with and without HF
The median (IQR) ages of the populations with and without HF were 81.1 (73.3-86.7) years and 65.2 (57.5-74.6) years, respectively, with the difference in mean (SD) ages (12.4 [95%CI: 10.8-14.0] years) between both populations being significant (p < 0.001) ( Table 2). The difference in the female percentage (1.9% [95%CI: 5.5-9.3]) between the populations with and without HF was non-significant (p = 0.619) ( Table 3). In the population with HF, the difference in mean (SD) age between males (80.2 [9.6] years) and females (77.2 [11.4] years) was close to statistical significance (p = 0.057). All quantitative clinical variables were significantly higher in the population with HF than in the population without HF, except for diastolic blood pressure, TC, HDL-C, non-HDL-C, LDL-C, non-HDL-C/HDL-C, and eGFR, which were significantly higher in the population without HF. The differences for systolic blood pressure, TG, VLDL-C, TG/HDL-C, triglyceride-glucose (TyG) index, and AST were non-significant ( Table 2).
All the ORs of the CVRFs and comorbidities showed a significant association with HF, except for overweight, abdominal obesity, increased WHtR, prediabetes, hypercholesterolaemia, hypertriglyceridaemia, and atherogenic dyslipidemia, whose differences were non-significant. The ORs for smoking, alcoholism and low, moderate and high CVR showed a significant association with the population without HF. A total of 97.2% [95%CI: 94.8-99.6] of the population with HF had a high or very high CVR according to SCORE [22] and SCORE-OP [23] ( Table 3). The multivariate analysis showed that the same variables independently associated with HF in the overall adult population were also associated in the population aged ≥50 years ( Table 4). The main results are summarized in the Graphical Abstract.

HF Prevalence Rates
The healthcare burden of HF is increasing worldwide, probably due to population ageing and lower mortality because of better management of the disease and its associated factors [8][9][10][11][12][13]. Consequently, the use of healthcare resources and hospitalizations readmissions, and outpatient visits due to HF have been increasing [16,[24][25][26]. Seferovic et al. [26] showed that the incidence of HF in Spain was 2.76 per 1000 person-years and the prevalence was 12.0 per 1000 persons. The adjusted prevalence rates of HF in the present study increased with age (R 2 = 0.911), from 2.1% in the population aged ≥18 years to 10.0% in the population aged ≥70 years, and was slightly higher in females in all age groups. HF cases are concentrated in the older age groups and are anecdotal in those under 50 years of age ( Figure 1). It should be noted that the mean age of the subjects with HF in the SIMETAP-HF study (78.4 years) is similar to the mean age found in Störk et al.'s study [27] (76.2 years). The prevalence rates in the PRICE study [28] ranged from 1.3% in the 45-54 age group to 16.1% in those older than 74 years. HF prevalence in the population over 50 years was 4.5%, whereas the PRICE study [28] showed a prevalence of 6.8% in the population over 45 years. We observed that women with HF were younger than men, both in the ≥50 years group ( , which is probably due to gender differences in terms of predominant etiology (CHD in men vs. HTN and DM in women) [29].

Clinical Conditions and Factors Associated with HF
In a review by Khan et al. [30], although the prevalence of smoking in patients with HF has been decreasing in recent years, hyperlipidemia, CHD, DM, HTN, CKD and AF have increased over time. The SIMETAP-HF study found that 22 comorbidities were more frequent in the population aged ≥18 years with HF than in non-HF, and they were reduced to 15 when the analysis focused on the population aged ≥50 years (Table 3). Loosen et al.'s study [31] showed that 36 previously defined comorbidities were more frequent in HF patients, but regression analysis showed that only 19 of them were significantly associated with it. The multifactorial analysis performed in SIMETAP-HF showed that sedentary lifestyle, HTN, DM AF, CHD, stroke, and low eGFR were the factors independently associated with HF (Table 4).
Physical inactivity has been associated with an increased risk of HF worsening and all-cause mortality in patients with HF [32]. In our study, 64% of patients with HF had a sedentary lifestyle, and this was independently associated with HF (OR 2.0).
There is a correlation between obesity and adiposity, especially abdominal fat, with cardiovascular disease [33]. The obesity and abdominal obesity prevalence rates were higher in patients with HF (41% and 61%, respectively) than in those without HF (27% and 44%, respectively). A study conducted in China showed that the highest WHtR values (≥0.5) constituted an independent risk factor for all-cause mortality, cardiovascular mortality and HF rehospitalization [34]. In patients with HF in the present study, the prevalence of elevated WHtR was 76%. Adiposity was also highly prevalent among HF patients in our study. The Jackson Heart study showed that visceral adiposity was associated with hospitalization for incident HF, pericardial adiposity and mortality [35].
HTN is the clinical condition most frequently associated with HF. A systematic review of HTN trials concluded that 28.9% of hypertensive patients had developed HF [36]. We found that more than 90% of patients with HF had HTN. Pulse pressure has also been linked to CVR [37]. Pulse pressure in the present study was higher in subjects with HF than in those without HF. Hypercholesterolemia and low HDL-C levels were also more common in HF patients. High levels of non-HDL cholesterol or low HDL-C levels are associated with the HF incidence [38].
Abnormal glucose regulation and DM maintain a close and bidirectional relationship with HF, and the presence of DM increases mortality and hospitalizations in patients with HF [39]. Up to 27% and 42% of patients with HF in the SIMETAP-HF study had prediabetes and DM, respectively. Insulin resistance is the link between DM and MetS. In our study, the MetS prevalence in patients with HF (82%) was similar to that shown in other studies [40].
AF is strongly associated with an increased risk of HF as these closely related pathologies that often coexist predispose to each other and share risk factors such as HTN, DM, CHD, and valve disease [41][42][43]. The present study shows a strong association of AF with HF (OR 11.5) due to the higher prevalence of AF in patients with HF (46.4%) than the Loosen et al., study [31] (18.6%). In order to better differentiate between the associations of the main clinical conditions or comorbidities with HF, Figure 2A,B show the results of multivariate analysis, including or not including AF, respectively. AF prevalence in the subjects with HF in our study (46%) is intermediate compared to that of other studies [32,42,43]. The differences are probably related to the study design, the age groups analyzed, the control of CVRFs associated with HF, and the greater or lesser availability of echocardiography or natriuretic peptides to diagnose HF in suspected cases.
Erectile dysfunction is an early predictor of cardiovascular events and HF, and HF itself can worsen sexual health due to its comorbidities. In our study, 71% of patients with HF had erectile dysfunction, similar to the other studies [44] (80%). The heart and kidneys act synergistically to maintain blood pressure and homeostasis such that any alteration of one of them leads to the deterioration of the other [45,46]. In the present study, the presence of low eGFR (48%) and CKD (55%) in patients with HF is in line with findings in the Löfman et al., study [47], in which 51% of FH patients had a low eGFR.
CHD is the main etiological factor in patients with HF [46,48]. The German EuroAspire IV cohort study [49] showed that 44.2% of patients with CHD had HF. Our study reports that about 30% of patients with HF had CHD, which is similar to the Swedish population and higher than the Chinese population [50]. The study by Loosen et al. [31] reported a lower association with HF (HR 1.5) probably because the median age of the population without HF (76 years) was much higher than that of our study (54.3 years).
of the main clinical conditions or comorbidities with HF, Figure 2A,B show the r multivariate analysis, including or not including AF, respectively. AF prevalenc subjects with HF in our study (46%) is intermediate compared to that of other [32,42,43]. The differences are probably related to the study design, the age grou lyzed, the control of CVRFs associated with HF, and the greater or lesser availa echocardiography or natriuretic peptides to diagnose HF in suspected cases. Erectile dysfunction is an early predictor of cardiovascular events and HF, itself can worsen sexual health due to its comorbidities. In our study, 71% of patie HF had erectile dysfunction, similar to the other studies [44] (80%). The heart and act synergistically to maintain blood pressure and homeostasis such that any alte one of them leads to the deterioration of the other [45,46]. In the present study, t The high prevalence of all these conditions, the metabolic, renal and cardiovascular factors suffered by patients with HF, and the mean age (78.4 years) justifies that more than 85% of the subjects have a very high CVR.

Strengths and Limitations
The main limitations of this study were the inability to determine causality or to estimate incidence rates, inter-interviewer variability, possible under-reporting in the medical records of the HF diagnosis, possible heterogeneity of the measurement and laboratory equipment, and HF underdiagnoses due to the per protocol exclusion of pregnant women, the terminally ill, and institutionalized or cognitively impaired patients. The main strengths include the population-based random selection, a large sample with people aged 18.0-102.8 years, the determination of both crude and adjusted prevalence rates of HF, and the assessment of the possible association of HF with numerous cardiometabolic and renal variables.

Clinical Implications
The high prevalence of HF in the population over 50 years of age entails serious socioeconomic and health consequences due to the increase in hospitalizations due to HF and cardiovascular mortality. Assessing the epidemiological magnitude of HF is essential to better plan prevention policies aimed at reducing the high healthcare and economic burden that it causes, both in primary care and in a hospital setting, to optimize available health resources and to improve medical care and quality of life for patients. HF is strongly influenced by age after 50 years, so its prevalence rates should always be age-adjusted to compare them with other populations. We hope that this study improves knowledge of HF prevalence and that it contributes to understanding the importance and magnitude of CVRFs and comorbidities associated with HF.

Conclusions
HF is a complex syndrome that constitutes a serious health problem worldwide, closely related to the aging of the population, which accumulates a constellation of comorbidities that accelerate its progression and increase the risk of mortality and hospitalization.
The assessment of the current prevalence of HF among the adult population and its association with ASCVD and CKD is crucial because it can help in the rational management of patients with HF. This study investigated the crude and adjusted prevalence rates of HF and its comorbid conditions. It confirmed the close relationship between age and the prevalence of HF, without differences by sex, being 2.1% in the adult population, 4.6% in those ≥50 years, and reaching 10% in those ≥70 years. The confluence of all the comorbidities independently associated with HF and the patients' ageing determined that their CVR was very high.
The early detection of HF-related comorbidities will allow the comprehensive management of HF, which would include healthy lifestyle modifications, and an approach to obesity, HTN, and DM, which would delay the worsening of HF and the development of AF, CKD, and ASCVD. • Heart failure prevalence rates vary according to the income and development of countries.

•
Although heart failure mortality is stabilizing over time, heart failure hospitalization is increasing due to population ageing, which carries a high economic and healthcare burden.

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There are many cardiometabolic and renal factors associated with heart failure.

What Does This Study Add?
• Heart failure is strongly influenced by age after 50 years. • Heart failure prevalence rates increase from 2.1% in the overall adult population to 10% in people over 70 years. • Physicians should be aware that atrial fibrillation, hypertension, diabetes, coronary heart disease, stroke, low estimated glomerular filtration rate and sedentary lifestyle are clinical conditions independently associated with heart failure.

•
Knowing the cardiometabolic and renal factors associated with heart failure would facilitate its early detection and management to reduce its severity and hospitalization rates.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/jcm12154924/s1, Figure S1: Causes, comorbidities and complications of heart failure; Table S1: Variables or clinical conditions criteria. Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.

Data Availability Statement:
Research data is available upon reasonable request.

Conflicts of Interest:
The authors declare no conflict of interest.